Orally Absorbed Pharmaceutical Formulation and Method of Administration

ABSTRACT

A pharmaceutical formulation for absorption through oral mucosae comprising an effective amount of (a) a pharmaceutical agent in mixed micellar form, (b) at least one micelle-forming compound selected from the group comprising an alkali metal alkyl sulfate and a polyoxyethylene sorbitan monooleate, (c) a block copolymer of polyoxyethylene and polyoxypropylene, (d) at least one additional micelle-forming compound, and (e) a suitable solvent. The invention also provides a metered dose dispenser (aerosol or non-aerosol) containing the present formulation and a method of administering insulin using the metered dose dispenser comprising administering split doses of a formulation containing insulin before and after each meal.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical formulations effectiveto deliver a pharmaceutical agent across oral membranes (e.g. buccal andpharyngeal mucosae) as well as to methods of administering, and metereddose dispensers containing, the pharmaceutical formulations.

BACKGROUND INFORMATION

Relatively little progress has been made over the years in reaching thetarget of safe and effective oral formulations for pharmaceuticalagents, especially macromolecular pharmaceutical agents such as peptidesand proteins. Barriers to developing oral formulations include poorintrinsic permeability, lumenal and cellular enzymatic degradation,rapid clearance, and chemical instability in the gastrointestinal (GI)tract. Pharmaceutical approaches to address these barriers that havebeen successful with traditional small, organic drug molecules have notreadily translated into effective macromolecular formulations.

Various routes of administration other than injection for very largemolecule drugs have been explored with little or no success. Oral andnasal cavities have been of particular interest. The ability ofmolecules to permeate the oral mucosae appears to be related tomolecular size, lipid solubility and peptide protein ionization.Molecules less than 1000 daltons appear to cross oral mucosae rapidly.As molecular size increases, the permeability of the molecule decreasesrapidly. Lipid soluble compounds are more permeable than non-lipidsoluble molecules. Maximum absorption occurs when molecules areunionized or neutral in electrical charges. Charged molecules,therefore, present the biggest challenges to absorption through the oralmucosae.

Most proteinic drug molecules are extremely large molecules withmolecular weights exceeding 5500 daltons. In addition to being large,these molecules typically have very poor lipid solubility, and are noteasily absorbed through oral or pulmonary mucosae. Substances thatfacilitate the absorption or transport of large molecules (which aredefined herein to mean molecules>1000 daltons) across biologicalmembranes are referred to in the art as “enhancers” or “absorptionaids”. These compounds generally include chelators, bile salts, fattyacids, synthetic hydrophilic and hydrophobic compounds, andbiodegradable polymeric compounds. Many enhancers lack a satisfactorysafety profile respecting irritation, lowering of the barrier function,and impairment of the mucocilliary clearance protective mechanism.

Some enhancers, especially those related to bile salts and some proteinsolubilizing agents, give an extremely bitter and unpleasant taste. Thismakes their use almost impossible for human consumption on a dailybasis. Several approaches attempting to address the taste problemrelating to the bile salt-based delivery systems include patches forbuccal mucosa, bilayer tablets, controlled release tablets, use ofprotease inhibitors, and various polymer matrices. These technologiesmay fail to deliver large molecule drugs in the required therapeuticconcentrations, however. Furthermore, the film patch dispensers resultin severe tissue damage in the mouth.

Other attempts to deliver large molecules via the oral, nasal, rectal,and vaginal routes using single bile acids or enhancing agents incombination with protease inhibitors and biodegradable polymericmaterials similarly often fail to achieve therapeutic levels of thesubject drug. Single enhancing agents often fail to loosen tightcellular junctions in the oral, nasal, rectal and vaginal cavities forthe time needed to permit passage of drug molecules through the mucosalmembranes without further degradation. These problems make itimpractical to use many systems.

Accordingly, there remains a need for therapeutic formulations that areuseful in oral applications, particularly those comprising largemolecule pharmaceutical agents. Methods of use of such formulations arealso needed.

SUMMARY OF THE INVENTION

The present invention addresses the above need by providing apharmaceutical formulation for absorption through oral mucosaecomprising an effective amount of (a) a large molecule pharmaceuticalagent in mixed micellar form, (b) trihydroxyoxocholanyl glycine or saltthereof, (c) glycerin, and (d) a suitable solvent.

In the present formulation, trihydroxyoxocholanyl glycine, a saltthereof, and glycerin are micelle-forming compounds. Preferably, thesalt of trihydroxyoxocholanyl glycine is sodium glycocholate.

The pharmaceutical formulation may further comprise at least oneadditional micelle-forming compound selected from the group comprisingalkali metal alkyl sulfates, block copolymers of polyoxyethylene andpolyoxypropylene, monooleates, polyoxyethylene ethers, polyglycerin,lecithin, hyaluronic acid, glycolic acid, lactic acid, chamomileextract, cucumber extract, oleic acid, linoleic acid, linolenic acid,monoolein, monolaurates, borage oil, evening primrose oil, menthol,lysine, polylysine, triolein, polidocanol alkyl ethers,chenodeoxycholate, deoxycholate, alkali metal salicylates (e.g. sodiumsalicylate), pharmaceutically acceptable edetates (e.g. disodiumedetate), and pharmaceutically acceptable salts and analogues thereof.

In yet another embodiment, the at least one additional micelle-formingcompound is selected from the group comprising alkali metal alkylsulfates, block copolymers of polyoxyethylene and polyoxypropylene,monooleates, polyoxyethylene ethers, lecithin, oleic acid, polyglycerin,chenodeoxycholate, deoxycholate, lactic acid and pharmaceuticallyacceptable salts and analogues thereof.

In one embodiment, the micelle-forming compounds comprise (i) at leastone of an alkali metal alkyl sulfate and a polyoxyethylene sorbitanmonooleate, and (ii) a block copolymer of polyoxyethylene andpolyoxypropylene.

The monooleates are preferably polyoxyethylene sorbitan monooleates and,more preferably, an (x)-sorbitan mono-9-octadecenoatepoly(oxy-1,2-ethanediyl) monooleate (e.g. a surfactant also known aspolysorbate 80, sold in association with the trademark, TWIN 80).

The micelle-forming compounds, including trihydroxyoxocholanyl glycine,a salt thereof, and glycerin, when present, are each present in aconcentration of from about 0.001 to 20 wt./wt. %, from about 0.001 to10 wt./wt. %, from about 0.001 to 5 wt./wt. %, from about 0.001 to 2wt./wt. %, from about 0.001 to 1 wt./wt. %, or from about 0.001 to 0.15wt./wt. %, of the total formulation.

Although not necessary, the pharmaceutical formulation may furthercomprise an effective amount of at least one stabilizer and/orpreservative (e.g. phenolic compound, sodium benzoate). Each of theseingredients, when present, may be present in a concentration of fromabout 0.01 to 10 wt./wt. %, or from about 0.1 to 7 wt./wt. %, or fromabout 0.1 to 5 wt./wt. %, or from about 0.1 to 3 wt./wt. %, of the totalformulation.

As well, one or more inorganic salts, antioxidants, protease inhibitors,and isotonic agents may also be added to provide necessary or desiredproperties. The selection of these ingredients and concentrationsthereof in the formulation will depend on the pharmaceutical agentemployed and is within the expertise of the person of ordinary skill inthe art.

The pharmaceutical agent is present in mixed micellar form in theformulation. The micelle size is equal to or greater than 7, 8, 9, 10,or 11 microns (μm). Preferably, the micelle size is equal to or lessthan 50, 40, 30, 15, or 11 microns. Particles of this size have beenfound to lead to reduced deposition of the pharmaceutical agent in thelungs and effective absorption by the oral membranes. Thus, absorptionof the pharmaceutical agent occurs mostly through the oral (e.g. buccaland pharyngeal) mucosae.

It is a further aspect of the invention to provide a metered dosedispenser (aerosol or non-aerosol) comprising the pharmaceuticalformulation. Preferably, the dispenser is an aerosol dispenser furthercomprising a pharmaceutically acceptable propellant which is liquidunder pressure within the dispenser.

According to a further aspect, the invention provides a method ofadministering the present pharmaceutical formulation comprising sprayingthe pharmaceutical formulation into the oral cavity of a patient usingthe metered dose dispenser.

When the pharmaceutical agent is insulin, the method may furthercomprise spraying the pharmaceutical formulation into the oral cavity ofa patient at intervals throughout the day to maintain blood glucoselevels within normal limits. This method is performed in addition toadministering insulin or an insulin analogue as part of a baselinetherapy. Preferably, the formulation is administered immediately beforeand after each of breakfast, lunch, dinner and snacks. The amount ofinsulin administered immediately before and after each meal may begreater than 14, 20, 26, 30 or 40 units and less than 110 or 85 units.

The formulation may also be administered between meals to achieve fineadjustment of glycemic levels. The amount of insulin administeredbetween meals may be greater than 14, 20 or 30 units and less than 80 or60 units.

The amount of insulin administered per dose and specific schedules willdepend on patient requirements as can be determined through bloodglucose monitoring.

The present invention satisfies the need for an easy and convenientmeans for controlling post-prandial glucose levels (i.e. blood glucoselevels at one and two hours after eating). Formulations according to thepresent invention, administered pre- and post-prandially give rise topharmacokinetic profiles which show a normalization of post-prandialglucose levels. There is data that correlates elevated post-prandialglucose levels with an increased risk for cardiovascular disease. Thus,controlling post-prandial glucose levels is expected to give rise tohealth benefits.

These and other aspects and advantages of the invention will be apparentfrom the following disclosure and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is further illustrated by the following non-limitingdrawings in which:

FIG. 1 is a front isometric view of a metered dose aerosol dispenserwhich can be used to deliver formulations according to the presentinvention.

FIG. 2 is a side view of an aerosol can and metering valve assembly forthe metered dose aerosol dispenser.

FIG. 3 is a cross-sectional side view of an actuator, aerosol can andmetering valve for the metered dose aerosol dispenser, showing themetering valve at rest.

FIG. 4 is a side cross-sectional view of an actuator, can and meteringvalve for the metered dose aerosol dispenser, showing the metering valveopen.

FIG. 5 is a graph in which average blood glucose levels are plotted as afunction of time to show the pharmacokinetic/pharmacodynamic (PK/PD)profiles of formulations according to the present invention when givenin single versus divided dose around meals and to compare thebioavailability of such formulations with injected insulin.

FIG. 6 is a graph in which average mean blood glucose concentrations areplotted as a function of time to compare the bioavailability of aformulation according to another embodiment of the invention withinjected insulin.

FIG. 7 is a graph in which average blood glucose levels are plotted as afunction of time to show the show the pharmacokinetic/pharmacodynamic(PK/PD) profiles of a formulation according to a further embodiment ofthe present invention when given in single versus divided dose aroundmeals and to compare the bioavailability of such formulation withinjected insulin.

DETAILED DESCRIPTION OF THE INVENTION

The term “comprising” when used herein means “including withoutlimitation.” Thus, a formulation or group comprising a number ofintegers may also comprise additional integers not specifically recited.The term “consisting essentially of” when used herein means includingthe recited integers and such additional integers as would notmaterially affect the basic and novel properties of the invention. Thebasic and novel properties of the invention are the absorptioncharacteristics of the present pharmaceutical agents through oralmucosae (e.g. buccal, pharyngeal, lingual, sublingual, and palatemucosae) into a patient's bloodstream.

The present pharmaceutical formulations comprise an “effective amount”of the pharmaceutical agent. As used herein, the term “effective amount”refers to that amount of the pharmaceutical agent needed to bring aboutthe desired result, such as obtaining the intended treatment orprevention of a disorder, or regulating a physiological condition in apatient. Such an amount will therefore be understood as having atherapeutic and/or prophylactic effect in a patient.

As used herein, the term “patient” refers to members of the animalkingdom, including but not limited to humans. It will be appreciatedthat the effective amount will vary depending on the particularpharmaceutical agent used, the nature and severity of the disorder beingtreated, and the patient being treated. The determination of whatconstitutes an effective amount is within the skill of one practising inthe art based upon the general guidelines provided herein.

For absorption through oral membranes, it is often desirable toincrease, such as by doubling or tripling, the dosage of pharmaceuticalagent which is normally required through injection or administrationthrough the gastrointestinal tract. In formulations containing insulinas the pharmaceutical agent, the amount of insulin administered per dosecan be increased as much as 10-fold as the bioavailability of sprayedinsulin is much lower.

Typically, the present formulations will contain pharmaceutical agentsin a concentration of from about 0.001 to 20 wt./wt. %, about 0.1 to 15wt./wt. %, about 0.1 to 10 wt./wt. %, about 0.1 to 5 wt./wt. %, or about0.1 to 1 wt./wt. %, of the total formulation.

The term “pharmaceutical agent” as used herein covers a wide spectrum ofagents, and can include agents used for both human and veterinaryapplications including but not limited to treatment and study. The termbroadly includes proteins, peptides, hormones, vaccines and drugs.

The term “macromolecular” or “large molecule” refers to pharmaceuticalagents having a molecular weight greater than about 1000 daltons;preferably the macromolecular pharmaceutical agents of the presentinvention have a molecular weight between about 2000 and 2,000,000daltons, although even larger molecules are also contemplated. When usedherein, “dalton” means 1/12 the mass of the nucleus of carbon-12 (i.e.equivalent to 1.657×10⁻²⁴ grams, also known as an “atomic mass unit”).

Preferred pharmaceutical agents include large molecule drugs of varyingsizes, including insulin, heparin, low molecular weight heparin(molecular weight less than about 5000 daltons), hirulog, hirugen,hirudin, interferons, cytokines, mono and polyclonal antibodies,immunoglobins, chemotherapeutic agents, vaccines, glycoproteins,bacterial toxoids, hormones, calcitonins, glucagon like peptides(GLP-1), large molecular antibiotics (i.e., greater than about 1000daltons), protein based thrombolytic compounds, platelet inhibitors,DNA, RNA, gene therapeutics, antisense oligonucleotides, opioids,narcotics, hypnotics, steroids and pain killers.

Hormones which may be included in the present formulations include butare not limited to thyroids, androgens, estrogens, prostaglandins,somatotropins, gonadotropins, erythropoetin, interferons, steroids andcytokines. Cytokines are small proteins with the properties of locallyacting hormones and include, but are not limited to, various forms ofinterleukin (IL) and growth factors including various forms oftransforming growth factor (TGP), fibroblast growth factor (FGF) andinsulin-like growth factor (IGF).

Vaccines which may be used in the formulations according to the presentinvention include bacterial and viral vaccines such as vaccines forhepatitis, influenza, tuberculosis, canary pox, chicken pox, measles,mumps, rubella, pneumonia, BCG, HIV and AIDS; bacterial toxoids includebut are not limited to diphtheria, tetanus, Pseudomonas sp. andMycobacterium tuberculosis. Examples of drugs, more specificallycardiovascular or thrombolytic agents, include heparin, hirugen, hirulosand hirudin. Pharmaceutical agents included in the present inventionfurther include monoclonal antibodies, polyclonal antibodies andimmunoglobins. These lists are not intended to be exhaustive.

A pharmaceutical agent that can be used in the present invention isinsulin, a very large molecule. “Insulin” used herein encompassesnaturally extracted human insulin, insulin extracted from bovine,porcine or other mammalian sources, recombinantly produced human,bovine, porcine or other mammalian insulin, insulin analogues, insulinderivatives, and mixtures of any of these insulin products. The termfurther encompasses the insulin polypeptide in either its substantiallypurified form, or in its commercially available form in which additionalexcipients are added. Various forms of insulin are widely commerciallyavailable. An “insulin analogue” encompasses any of the insulins definedabove wherein one or more of the amino acids within the polypeptidechain has been replaced with an alternative amino acid, wherein one ormore of the amino acids have been deleted, or wherein one or more aminoacids is added. “Derivatives” of insulin refers to insulin or analoguesthereof wherein at least one organic substituent is bound to one or moreof the amino acids in the insulin chain.

As mentioned above, the pharmaceutical agent exists in mixed micellarform in the present pharmaceutical formulation. As will be appreciatedby those skilled in the art, a micelle is a colloidal aggregate ofamphipathic molecules in which the polar hydrophilic portions of themolecule extend outwardly while the non-polar hydrophobic portionsextend inwardly, or vice versa depending on the hydrophilic-lipophilicbalance of the micelle forming compounds and type of solvent andpharmaceutical agent used. As discussed below, various combinations ofmicelle-forming compounds are utilized in order to achieve the presentformulation. It is believed that the presence of the micellessignificantly aids in the absorption of the pharmaceutical agent bothbecause of their enhanced absorption ability, and also because of theirsize. In addition, encapsulating pharmaceutical agents in micellesprotects the agents from rapid degradation in a hostile environment.

As used herein the term “mixed micelles” refers to either (a) at leasttwo different types of micelles each of which has been formed using oneor more micelle-forming compounds; or (b) one type of micelle formedwith at least two micelle-forming compounds. For example, the presentformulation may comprise a mix of at least two different types ofmicelles: micelles formed between the pharmaceutical agent and sodiumglycocholate and micelles formed between the pharmaceutical agent andglycerin. However, it may also comprise micelles wherein each micelle isformed from these two or more micelle-forming compounds. The mixedmicelles of the present invention tend to be smaller than the pores ofthe membranes in the oral cavity. It is therefore believed that theextremely small size of the present mixed micelles helps theencapsulated pharmaceutical agent penetrate efficiently through the oralmucosae. Thus, the present formulations offer increased bioavailabilityof active drug when compared with pharmaceutical preparations known inthe art.

The shape of the micelle can vary and be, for example, prolate, oblateor spherical; spherical micelles are most typical.

As mentioned above, the formulation may further comprise at least oneadditional micelle-forming compound selected from the group comprisingalkali metal alkyl sulfates, block copolymers of polyoxyethylene andpolyoxypropylene, monooleates, polyoxyethylene ethers, polyglycerin,lecithin, hyaluronic acid, glycolic acid, lactic acid, chamomileextract, cucumber extract, oleic acid, linoleic acid, linolenic acid,monoolein, monolaurates, borage oil, evening primrose oil, menthol,lysine, polylysine, triolein, polidocanol alkyl ethers,chenodeoxycholate, deoxycholate, alkali metal salicylates (e.g. sodiumsalicylate), pharmaceutically acceptable edetates (e.g. disodiumedetate), and pharmaceutically acceptable salts and analogues thereof.

Any alkali metal alkyl sulfate can be used in the present formulations,provided compatibility problems do not arise. Preferably, the alkyl is aC8 to C22 alkyl, more preferably lauryl (C12). Any alkali metal can beutilized, with sodium being preferred.

A particularly preferred block copolymer is that which has the followingformula:

HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H

-   -   wherein a=12 and b=20. This compound is sold by BASF of Mount        Olive N.J. in association with the trademark PLURONIC L44.

Other suitable block copolymers which can be used are those wherein a=12to 101 and b=20 to 56. For example, useful block copolymers availablefrom BASF are those sold in association with the trademarks PLURONIC F68(wherein a=80; b=27), PLURONIC F87 (wherein a=64; b=37), PLURONIC F108(wherein a=141 b=44), and PLURONIC F127 (wherein a=101 b=56).

The lecithin can be saturated or unsaturated, and is preferably selectedfrom the group consisting of phosphatidylcholine, phosphatidylserine,sphingomyelin, phosphatidylethanolamine, cephalin, and lysolecithin.

Preferred salts of hyaluronic acid are alkali metal hyaluronates,especially sodium hyaluronate, alkaline earth hyaluronates, and aluminumhyaluronate. When using hyaluronic acid or pharmaceutically acceptablesalts thereof in the present formulations, a concentration of betweenabout 0.001 and 5 wt./wt. % of the total formulation is preferred, morepreferably less than about 3.5 wt./wt. %.

For delivery of the present pharmaceutical agents, particularly verylarge molecules such as insulin, use of three or more micelle-formingcompounds is preferred as it achieves a cumulative effect in which theamount of pharmaceutical agent that can be delivered is greatlyincreased as compared to when only one or two micelle-forming compoundsare used. Use of three or more micelle-forming compounds also enhancesthe stability of the pharmaceutical agent formulations.

Particularly suitable micelle-forming compound combinations include eachof i) a block copolymer of polyoxyethylene and polyoxypropylene,glycerin, sodium glycocholate, and sodium lauryl sulfate; ii) apolyoxyethylene ether, glycerin, sodium glycocholate, and sodium laurylsulfate; iii) glycerin, sodium glycocholate and polyoxyethylene sorbitanmonooleate; iv) glycerin, sodium glycocholate, sodium lauryl sulfate andoleic acid; v) chenodeoxycholate, sodium glycocholate, sodium laurylsulfate, and glycerin; vi) deoxycholate, sodium glycocholate, sodiumlauryl sulfate, and glycerin; vii) glycerin, sodium glycocholate, sodiumlauryl sulfate, deoxycholate, and lactic acid; vii) glycerin, sodiumlauryl sulfate and sodium glycocholate; and viii) glycerin and sodiumglycocholate.

It will be appreciated that several of the micelle-forming compounds aregenerally described as fatty acids, bile acids, or salts thereof. Thebest micelle-forming compounds to use may vary depending on thepharmaceutical agent used and can be readily determined by one skilledin the art. In general, bile salts are especially suitable for use withhydrophilic drugs and fatty acid salts are especially suitable for usewith lipophilic drugs. Because the present invention uses relatively lowconcentrations of bile salts, problems of toxicity associated with theuse of these salts is minimized, if not avoided.

The above-described components of the present formulation are containedin a suitable solvent. The term “suitable solvent” is used herein torefer to any solvent in which the components of the present inventioncan be solubilized, in which compatibility problems do not arise, andwhich can be administered to a patient. Any suitable aqueous ornonaqueous solvent can be used such as water and alcohol solutions (e.g.ethanol). Alcohol should be used at concentrations that will avoidprecipitation of the components of the present formulations. Enough ofthe solvent should be added so that the total of all of the componentsin the formulation is 100 wt./wt. %, i.e., solvent to q.s. Typically,some portion of the solvent will be used initially to solubilize thepharmaceutical agent prior to the addition of the micelle-formingcompounds. Embodiments of pharmaceutical formulations containing insulinemploy aqueous solvents. The pH of the solution is typically in therange of 5 to 8, 6 to 8, or 7 to 8. Hydrochloric acid or sodiumhydroxide can be utilized to adjust the pH of the formulation as needed.

The present formulations optionally contain a stabilizer and/or apreservative (e.g. sodium benzoate and phenolic compounds). Phenoliccompounds are particularly suited for this purpose as they not onlystabilize the formulation, but they also protect against bacterialgrowth. It is also believed that phenolic compounds aid in absorption ofthe pharmaceutical agent. A phenolic compound will be understood asreferring to a compound having one or more hydroxy groups attacheddirectly to a benzene ring. Preferred phenolic compounds according tothe present invention include phenol, o-cresol, m-cresol, and p-cresol,with phenol and m-cresol being most preferred.

The formulations of the present invention can further comprise one ormore of the following: inorganic salts, antioxidants, proteaseinhibitors, and isotonic agents. The amount of any of these optionalingredients to use in the present formulations can be determined by oneskilled in the art. It will be understood by those skilled in the artthat colorants, flavoring agents and non-therapeutic amounts of othercompounds may also be included in the formulation. Typical flavoringagents are menthol, sorbitol and fruit flavours. When menthol is used asone of the micelle-forming compounds, it will also impart flavour to thecomposition.

In formulations containing insulin, inorganic salts may be added thatopen channels in the GI tract thereby providing additional stimulationto release insulin in vivo. Non-limiting examples of inorganic salts aresodium, potassium, calcium and zinc salts, especially sodium chloride,potassium chloride, calcium chloride, zinc chloride and sodiumbicarbonate. When used, the inorganic salts are typically in aconcentration of from about 0.001 to about 10 wt./wt. % of the totalformulation.

It will be recognized by those skilled in the art that for manypharmaceutical formulations it is usual, though optional, to add atleast one antioxidant to prevent degradation and oxidation of thepharmaceutically active ingredients. The antioxidant can be selectedfrom the group consisting of tocopherol, deteroxime mesylate, methylparaben, ethyl paraben, ascorbic acid and mixtures thereof, as well asother antioxidants known in the pharmaceutical arts. A preferredantioxidant is tocopherol. The parabens will also provide preservationto the formulation. When used, the antioxidants are typically in aconcentration of from about 0.001 to about 10 wt./wt. % of the totalformulation.

Protease inhibitors serve to inhibit degradation of the pharmaceuticalagent by the action of proteolytic enzymes. When used, proteaseinhibitors are preferably in a concentration of between about 0.1 and 3wt./wt. % of the total formulation. Any material that can inhibitproteolytic activity can be used, absent compatibility problems.Examples include but are not limited to bacitracin and bacitracinderivatives such as bacitracin methylene disalicylates, soybean trypsin,and aprotinin. Bacitracin and its derivatives are preferably used in aconcentration of between 1.5 and 2 wt./wt. % of the total formulation,while soyabean trypsin and aprotinin are preferably used in aconcentration of between about 1 and 2 wt./wt. % of the totalformulation.

An isotonic agent such as glycerin or dibasic sodium phosphate may alsobe added after formation of the mixed micellar formulation. The isotonicagent serves to keep the micelles in solution. When glycerin is used asa micelle-forming compound, it also functions as an isotonic agent. Whendibasic sodium phosphate is used it will also serve to inhibit bacterialgrowth.

The formulations of the present invention may be stored at roomtemperature or at cold temperature (i.e. from about 2 to 8° C.). Storageof proteinic drugs is preferable at a cold temperature to preventdegradation of the drugs and to extend their shelf life.

The present invention, therefore, provides a novel and inventivepharmaceutical formulation in which a pharmaceutical agent isencapsulated in mixed micelles formed by a combination ofmicelle-forming compounds. The formulation can be delivered through oralmembranes, e.g. pharyngeal, sublingual and buccal mucosae. Thepharyngeal mucosae is the lining of the posterior of the oral cavity,i.e. the upper the part of the throat that is located below the softpalate and above the larynx, the sublingual mucosa includes the membraneof the ventral surface of the tongue and the floor of the mouth, and thebuccal mucosa is the lining of the cheeks. The pharyngeal, sublingualand buccal mucosae are highly vascularized and permeable, allowing forthe rapid absorption and acceptable bioavailability of many drugs. Incomparison to the GI tract and other organs, the oral environment haslower enzymatic activity and a neutral pH that allows for a longereffective life of the drug in vivo. The pharyngeal, sublingual, lingual,palate and buccal mucosae are collectively referred to herein as the“oral mucosae”.

Absorption of the pharmaceutical agent through oral mucosae offers anumber of advantages, including the avoidance of the first pass effectof hepatic metabolism and degradation of the drug within the hostile GIenvironment, easy or convenient access to membrane sites; and a painfree form of administration (as compared to administration bysubcutaneous injection).

Preferably, the present formulations are delivered through aerosol ornon-aerosol dispensers capable of delivering a precise amount ofmedication with each application. Aerosol dispensers are charged with apharmaceutically acceptable propellant. Such dispensers are known forpulmonary drug delivery for some drugs (e.g. asthma medications).Non-aerosol dispensers include spray pumps and drop dispensers.

One benefit of using a metered dose aerosol dispenser is that thepotential for contamination is minimized because the dispenser isself-contained. Moreover, the propellant provides improvements inpenetration and absorption of the present mixed micellar formulations.They may be selected from the group comprising C₁ to C₂ dialkyl ether,butanes, fluorocarbon propellant, hydrogen-containing fluorocarbonpropellant, chlorofluorocarbon propellant, hydrogen-containingchlorofluorocarbon propellant, other non-CFC and CFC propellants, andmixtures thereof. Examples of suitable propellants includetetrafluoroethane (e.g. HFA 134a which is 1,1,1,2 tetrafluoroethane),heptafluoroethane, dimethylfluoropropane, tetrafluoropropane, butane,isobutane, dimethyl ether and diethyl ether.

The propellant is a liquid under pressure and causes the pharmaceuticalformulation to be propelled from a metered dose aerosol dispenser in afine spray. The dispenser has a metered dose valve of which theassociated metering chamber is of a size that is preferably equal to orgreater than about 10, 50, 250, 540 or 570 μl but equal to or less thanabout 660 or 630 μl. In embodiments containing insulin, the valve ispreferably from about 540 to 660 μl in size, though the size may be assmall as 50 μl.

The amount of propellant to be added to the metered dose aerosoldispenser will depend on a number of factors including the size of thepressurized container and the amount of pharmaceutical formulationcontained therein. The amount of the propellant is selected to provideadministration of a suitable amount of the pharmaceutical agent peractuation, while avoiding undesirable events such as foaming. In oneembodiment wherein the pharmaceutical agent is insulin, the amount ofpharmaceutical formulation is from 50, 67, 71, 77, or 83 parts per 1000parts of the total composition in the container (i.e. pharmaceuticalformulation plus propellant). Preferably, the amount of pharmaceuticalformulation is less than or equal to 91 parts per 1000 parts of thetotal composition in the container.

The amount of pharmaceutical agent emitted per actuation of thedispenser or dispenser will vary according to a number of factorsincluding the nature and amount of pharmaceutical formulation in thecontainer, nature and amount of propellant in the container, size ofcontainer and size of metering valve of the dispenser.

The present formulations may be prepared by mixing the pharmaceuticalagent with the micelle-forming compounds and optional stabilizers andother additives in a suitable solvent. The compounds may be added in onestep or sequentially. When added sequentially, they can be added in anyorder provided solubility issues do not arise. Mixed micelles will formwith substantially any kind of mixing of the ingredients but vigorousmixing is preferred in order to provide micelles of from about 7 to 11microns in size. Vigorous mixing may be accomplished by using high-speedstirrers, such as magnetic stirrers, propeller stirrers, or sonicators.

In one embodiment, a pharmaceutical formulation containing insulin,Solution III, is prepared by making two solutions, Solutions I and II,and then mixing them together and with a solvent in accordance with thefollowing protocol.

Preparation of Solution I

Solution I, a bulk insulin solution containing 200 units of insulin, isprepared as follows. Absolute amounts of each ingredient in Solutions I,II and III can be calculated based on the final batch size of SolutionIII. Note that the amount of units of insulin per mg of commercialinsulin varies with the commercial insulin product generally betweenabout 25.3 and 28.3 units per mg of insulin. Knowledge of the number ofunits per mg is readily determinable from product specifications.

-   If necessary, adjust pH with 5M NaOH or 7M HCl until a solution pH    of between 7-8 is reached.

Preparation of Solution II

Solution II is an aqueous solution of micelle-forming compounds to beadded to Solution I.

Add 2.00 w/w % block copolymer of polyoxyethylene and polyoxypropylenehaving the formula:

HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H

wherein a=12 and b=20 (sold by BASF in association with the trademarkPLURONIC L44) and stir continuously until dissolved.

Preparation of Insulin Formulation (Solution III)

Solution III is a pharmaceutical formulation according to one embodimentof the invention. It is prepared as follows.

Transfer the solution into a storage beaker and stir solution for about5 minutes. Store at 2-8° C.

Metered Dose Aerosol Dispenser Comprising Solution III

In accordance with one aspect, the invention also provides a metereddose aerosol dispenser containing a formulation (e.g. Solution III)according to the invention.

In one embodiment, the invention employs the metered dose aerosoldispenser shown in FIGS. 1 to 4. The metered dose aerosol dispenser 10includes an actuator 12, 28 ml aluminum aerosol can 14, and a meteringvalve 16. 2 ml of Solution III is put into the aerosol can 14 accordingto a known method. The can 14 is then charged with about 27.06 grams ofHFA-134a propellant also in a known manner.

The aerosol can 14 is best illustrated in FIGS. 2-4. The aerosol can 14is preferably cylindrical having an open end 18. The open end 18 isdimensioned and configured to mate with the ferrule (described below) ofthe metering valve 16. While the can 14 is aluminum in this embodiment,stainless steel can also be used.

Referring to FIGS. 3 and 4, the metering valve 16 includes a 3-slothousing 20 with a stem 22 slidably contained therein. A preferredmaterial for the 3-slot housing and stem is Polyester, but acetal resinscan be used as well. The metering valve 16 also includes a ferrule 24,dimensioned and configured to fit around the outside of the open end 18of the aerosol can 14, being crimped around the end 18 to secure themetering valve to the can. A preferred material for the ferrule isaluminum. A sealing gasket 26 provides a seal between the can's open end18 and the ferrule 24. A preferred material for the sealing gasket isNitrile (Buna) rubber. A metering chamber 28 within the 3-slot housing20 is defined between the first stem gasket 30 and the second stemgasket 32. A preferred material for the first and second stem gaskets isNitrile (Buna) rubber. The stem includes an upper stem and a lower stem,with the upper stem having a U-shaped retention channel 34 having ends36 and 38, and the lower stem having a channel 40 having ends 42 and 44.The principle of retention lies in the particular geometry at the baseof the stem, which allows the passage of the fluid under thedifferential pressure from the aerosol can to valve metering chamberafter actuation, but prevents the return (due to gravity) of the fluidto the aerosol can by the capillary action of the retention channel.

The stem 22 moves between the rest (closed) position and an openposition. Within the rest position, shown in FIG. 3, the inlet end 36 ofthe retention channel 34 is above the first stem gasket 30, so that thecontents of the aerosol can 14 may enter the retention channel 34. Theoutlet end 38 of the retention channel 34 is below the first stem gasket30 and within the metering chamber 28. Both the inlet end 42 and outletend 44 of the channel 40 are outside the metering chamber 28, therebypreventing passage of fluid from the metering chamber 28 to the channel40. In the open position, shown in FIG. 4, both the inlet end 36 andoutlet end 38 of the retention channel 34 are above the first stemgasket 30 of the metering chamber 28, thereby preventing any fluid flowfrom the aerosol can 14 to the metering chamber 28. At the same time,the inlet end 42 of the channel 40 is above the second stem gasket 32and inside the metering chamber 28, thereby permitting passage of fluidfrom the metering chamber 28 through the passage 40. The stem 22 isbiased by the spring 46 into the rest position of FIG. 3. The meteringchamber 28 within the metering valve 16 may hold a total volume ofapproximately 600 μl. The large dose is necessary because largemolecules like insulin are poorly absorbed through the epithelialmembrane, easily destroyed by enzymes found in saliva, and arerelatively insoluble. Therefore, more medication needs to be deliveredto the buccal cavity to compensate for these losses.

The actuator assembly 12 is best illustrated in FIGS. 1, 3, and 4. Theactuator 12 includes a mouthpiece 50, a stem block 48 and an actuatorsump 52. The actuator sump 52, which is located in the stem block 48,includes an inlet end 54, dimensioned and configured to receive thelower end 56 of the valve stem 22, and an outlet end 58, called a sprayorifice. The spray orifice 58 of the actuator sump 52 is dimensioned andconfigured to direct medication towards the buccal cavity and back ofthe throat. The spray orifice 58 may have a round configuration, or mayhave an oval, rectangular, or similar elongated configuration, therebydirecting medication to either side of the mouth, increasing thelikelihood of medication hitting the buccal cavity. Some preferredembodiments will have a spray orifice 58 having a diameter ofapproximately 0.58 to 0.62 mm. A preferred configuration for theactuator sump 52 is a substantially reduced volume not more than 45 mm³.More preferred actuator sumps have a volume not exceeding 42 mm³, andideally the actuator sumps will have a volume not exceeding 37 mm³. Thesump volumes given above will be sufficient to generate a high-pressurestream of fluid upon actuation of the metered dose aerosol dispenser.

The actuator 12 may also include a cap 60, fitting over the actuator 12and aerosol can 14. The cap 60 is preferably slidably and removablysecured to the actuator 12. One method of slidably and removablysecuring the cap 60 to the actuator 12 is by friction, therebypermitting removal or reattachment of the cap 60 and actuator 12 bymerely pulling upward on the cap 60. The actuator 12 may also include adust cover 68, dimensioned and configured to cover the mouthpiece 50.

In this embodiment, the propellant, which is under pressure, is inliquid form in the can and forms a single phase with Solution III.However, in other embodiments having a different ratio of thepharmaceutical formulation to the propellant, the aqueous phase mayseparate from the propellant phase. In such case, it is recommended thatthe user shake the dispenser prior to dispensing a portion of thecontents.

When the actuator is actuated, Solution III, containing insulin, ispropelled from the metered dose valve in a fine spray. In thisembodiment about 7 to 13 units of insulin (average 10 units) are emittedper actuation. This is equivalent to about 0.27 mg to about 0.50 mg ofinsulin dispensed per actuation.

Further details concerning Solution III and the metered dose aerosoldispenser 10 are summarized in Table I below.

TABLE I Formulation per Can 400 units of Insulin/Can % w/w Formulation %w/w (based on (excluding g per 2 mL in (based on formulation propellant)Can (excluding propellant plus excluding per/actuation Solution III gper mL propellant) formulation) propellant) (g) insulin (200 units)0.0077 0.0144 0.050 0.77 0.00036 Glycerin 0.0025 0.0050 0.017 0.250.00013 Na glycocholate 0.0006 0.0012 0.004 0.06 0.00003 sodium laurylsulfate 0.0002 0.0004 0.001 0.02 0.00001 Pluronic L44 0.0200 0.04000.138 2.0 0.00100 injection water .9690 1.939 6.672 96.9 0.04848 134(a)HFA propellant 13.53 27.060 93.118 0.67650

Other Embodiments of the Formulation

Alternative embodiments of formulations according to the presentinvention are summarized in the below tables. In these tables, POE(9) ispolyoxyethylene 9 lauryl ether.

TABLE II Formulation # Solution IV Solution V Units insulin 1250 625 %w/w % w/w Insulin 4.650 2.370 Glycerin 4.830 4.930 Na glycocholate 0.2900.300 sodium lauryl sulfate 0.290 0.300 Phenol 0.290 0.300 m-cresol — —POE(9) 2.420 2.460 Pluronic L44 — — injection water 87.240  89.350 

TABLE III Formulation # Solution VI Solution VII Units insulin 200 200 %w/w % w/w Insulin 0.77 0.77 Glycerin 0.25 0.25 Na glycocholate 0.06 0.06Sodium lauryl sulfate 0.02 0.02 Phenol 0.2 0.1 m-cresol — — POE(9) — —Pluronic L44 2 2 injection water 96.7 96.8

TABLE IV Formulation # Solution VIII Solution IX Solution X Unitsinsulin 3000 2100 1000 % w/w % w/w % w/w Insulin 11.180 7.452 3.86Glycerin 0.048 0.25 0.25 Na glycocholate 0.003 0.058 0.06 Sodium laurylsulfate 0.003 0.02 0.02 Phenol 0.290 0.193 0.2 m-cresol — — — POE(9) — —— Pluronic L44 — 2 2 injection water 88.480 90.027 93.61

TABLE V Formulation # Solution XI Solution XII Solution XIII Unitsinsulin 3000 3000 3000 % w/w % w/w % w/w Insulin 11.180 11.180 11.570Glycerin 4.830 4.830 4.830 Na glycocholate 0.480 0.390 0.290 Sodiumlauryl sulfate — 0.015 0.015 Phenol 0.290 0.290 0.290 m-cresol — — —POE(9) — — — Pluronic L44 — — — injection water 83.220 83.300 83.400

TABLE VI Formulation # Solution XIV Solution XV Solution XVI Unitsinsulin 2500 3000 3000 % w/w % w/w % w/w Insulin 9.300 11.178 11.180glycerin 5.000 4.831 4.830 Na glycocholate 0.300 0.290 0.060 Sodiumlauryl sulfate 0.300 0.290 0.020 Phenol 0.300 0.290 0.290 m-cresol — — —POE(9) 2.240 2.415 — Pluronic L44 — — — injection water 82.590 80.70683.620

Method of Administration

The present invention also provides a method for administering thepharmaceutical formulation of the present invention, by spraying theformulation into the mouth with a metered dose dispenser (aerosol ornon-aerosol).

The following examples are intended to illustrate the methods of theinvention, and should not be considered as limiting the invention in anyway.

Example 1

A study was done to determine the difference in thepharmacokinetic/pharmacodynamic (PK/PD) profiles of Solution IV whengiven in a single versus a divided dose around meals. The study was alsodone to compare the bioavailability and glucodynamic profile of SolutionIV and V (given as a split dose) with injected insulin, Humulin™ brandinsulin (recombinantly produced human insulin sold by Eli Lilly andCompany). This study involved the following phases.

Transfer Phase

In this phase, 19 qualified patients (i.e. meeting certain healthcriteria) were given varying doses of Solution IV over the course ofthree days to determine the appropriate dose for each patient asfollows:

On day one, the patients were given 16 puffs of Solution IV administeredover an 8-minute period immediately prior to the test meal (a liquidstandardized meal, Ensure Plus: 20 kCal/kg ideal body weight), with onepuff administered every 30 seconds for a total of 16 puffs. Glucosemonitoring was done immediately before the test meal (−30 minutes),immediately prior to (0 minutes), and 5, 15, 30, 45, 60, 90, 120, 150,180, 210, and 240 minutes after the breakfast test dose.

On the second day of this phase, patients were given a single dose of 13puffs of Solution IV administered over a 6.5-minute period immediatelyprior to the test meal, with one puff administered every 30 seconds.Glucose levels were monitored as on the previous day.

On the third day of this phase, patients were given a single dose of 10puffs of Solution IV administered over a 5-minute period immediatelyprior to the test meal, with one puff administered every 30 seconds.Glucose levels were monitored as on the previous day.

Any patient dosed at 16 puffs and having a glucose level of 200 mg/dL atany time point or three consecutive levels greater than 180 mg/dL werenot allowed to participate in the Crossover Treatment Phase.

Crossover Treatment Phase

In this phase, the same 19 patients were exposed to each of thefollowing four treatment regimens on different days:

-   -   Humulin™ brand insulin (injected insulin)    -   Solution IV single dose—pre-meal    -   Solution IV split dose —½ pre-meal and ½ post-meal    -   Solution V split dose—½ pre-meal and ½ post-meal

Each treatment regimen was administered over a 24 hour period.

The single dose regimen involved administering 16 puffs of Solution Vover an 8 minute period, with one puff administered every 30 seconds.The first puff was timed such that the last puff was received 30 secondsbefore the test meal.

In respect of the split dose regimen for Solution IV, Solution IV wasadministered 4 minutes prior to the meal for the first ½ dose (1 puffevery 30 seconds, for a total of 8 puffs, with a 30 second intervalbetween the last puff and the test meal). Immediately after finishingthe standardized meal, the patient was given two sips of water andreceived the second ½ dose (8 puffs every 30 seconds) starting at about2 minutes after completion of the meal.

In respect of the split dose regimen for Solution V, Solution V wasadministered 4 minutes prior to the meal for the first ½ dose (1 puffevery 30 seconds, for a total of 8 puffs, with a 30 second intervalbetween the last puff and the test meal). Immediately after finishingthe standardized meal, the patient was given two sips of water andreceived the second ½ dose (1 puff every 30 seconds, for a total of 8puffs) starting at about 5 minutes after completion of the meal.

Each puff of Solution IV contained, on average, about 50 units ofinsulin.

Each puff of Solution V contained, on average, about 25 units ofinsulin.

For comparison purposes, 5 units of Humulin™ brand insulin were injected15 minutes prior to meals to the same group of 19 patients on adifferent day.

During the Crossover Treatment Phase, patients consumed 3 standardizedmeals (a liquid standardized meal, Ensure Plus: 20 kCal/kg ideal bodyweight) on each of the treatment periods. The standardized meal wasconsumed in four equal volumes over a 30 minute period.

During each treatment period, blood samples were drawn at −30 minutes,immediately prior to (0 minutes) and 5, 15, 30, 45, 60, 90, 120, 150,180, 210, and 240 minutes after the breakfast test dose. Glucose andinsulin levels were measured from each blood sample.

The average blood glucose levels for each group were plotted in a graphshown in FIG. 5. In this graph, the blue line represents Solution IVgiven as a split dose, the green line represents the Solution V given asa split dose, the orange line represents Solution IV given as a singledose, and the black line (circle points) represents Humulin brandinsulin given by injection.

As can be seen in this figure, Solutions IV and V are effective atcontrolling blood glucose levels with the split dose of Solution IVachieving slightly better results than the single dose of Solution IV.

Example II

A 12-day study was done to compare the efficacy of Solution III withinjected insulin and to evaluate the safety and tolerability of SolutionIII. The study compared the effect on blood glucose levels of SolutionIII administered to the buccal cavity using the above described metereddose aerosol dispenser, with the effect on blood glucose levels ofinjected insulin. Fructosamine, a parameter of protein glycation, wasdetermined as part of a panel of safety monitoring.

10 patients with Type-1 diabetes mellitus, who had 2 consecutive daysduring which fasting glucose levels were below 140 mg/dL and 1-hourpostprandial glucose levels were below 200 mg/dL, participated in thestudy.

During the 12 day study period, the patients received their usualbaseline glargine insulin therapy (⅔ in the morning and ⅓ in theevening).

On the first three days, each patient received his or her regular doseof Humulin™ brand insulin (recombinantly produced human insulin sold byEli Lilly and Company) by injection 30 minutes before each of threemeals: breakfast, lunch and dinner. The amount of insulin injectedvaried with the patient based on 0.1 units of insulin per kilogram bodyweight. Patients were also allowed mid-morning and mid-afternoon snacksand had the option of administering up to 4 units at snack-time.Patients opting to administer treatment at snack-time recorded thesnack-time dose on individual diary cards.

On days 4 to 12, each patient received from five to eight puffs ofSolution III, based on their recommended dose (as determined throughprior experiments) before and after each meal (breakfast, lunch anddinner). Solution III was administered to the buccal cavity using theabove described metered dose aerosol dispenser. An additional singledose following each meal of up to 4 puffs was allowed for immediateadministration if measured glucose value exceeded 100 mg/dL at 30 to 60minutes after the end of the meal. Thus, the total maximum dose ofSolution III relating to each meal was 20 puffs (or up to 60 puffsdaily).

In addition to the three meals a day, the patients were allowedmid-morning and mid-afternoon snacks. Patients were allowed toadminister up to 5 puffs at snack-time as a divided dose (e.g. 2 puffsbefore and 2 or 3 puffs after the snack).

Each puff of Solution III contained, on average, about 10 units ofinsulin.

On all 12 days, blood samples were drawn beginning 30 minutes beforebreakfast and ending 4 hours after breakfast. A standardized meal(Ensure Plus: 4.8 kCal/kg ideal body weight) was served for breakfast at8:00 AM (0 minutes). Blood samples were drawn at −30 minutes,immediately prior to (0 minutes) and 5, 15, 30, 45, 60, 90, 120, 150,180, 210, and 240 minutes after breakfast. Peripheral glucoseconcentrations were determined in duplicate by the Roche Accu-Checksystem. Duplicate measurements of glycosylated hemoglobin (HbA1_(c-II))and fructosamine were also obtained using Roche commercial assays.

The study protocol required that the pre-prandial glucose levels be lessthan 100 mg/dL. Thus, adjustments of glycemia at mid-morning, andmid-afternoon were done using common snacks, additional subcutaneousinjections of Humulin™ brand insulin or puffs of Solution III as notedabove.

The average mean blood glucose concentrations resulting from this studywere plotted on a graph shown in FIG. 6. In this figure, the black lineshows the mean blood glucose concentrations for the 10 patients as afunction of time, averaged over the first three days during whichinsulin was administered by injection. The red line shows the mean bloodglucose concentrations for the 10 patients as a function of time,averaged over days 4 to 12 during which Solution III was administeredusing the above described metered dose aerosol dispenser.

FIG. 6 shows that Humulin™ brand injected insulin and Solution IIIinduced similar glucodynamic responses. Solution III provided anappropriate glycemic control as assessed by individual daily-glycemiccurves and, especially, normal preprandial glycemia. Measurements ofprotein glycation displayed a tendency towards lower values after the12-day study period. This suggests that Solution III is safe for longterm use.

Example III

A study similar to that described in Example I was done to determine thedifference in the pharmacokinetic/pharmacodynamic (PK/PD) profiles ofSolution XIV (listed in Table VI above) when given in single versusdivided dose around meals. The study was also done to compare thebioavailability and glucodynamic profile of Solution XIV with injectedinsulin, Humulin™ brand insulin (recombinantly produced human insulinsold by Eli Lilly and Company). In this study, the same protocol and 19patients described in Example I above was employed.

The results were plotted on a graph shown in FIG. 7. This figure showsthat Solution XIV when administered as a split dose produces aglucodynamic profile that is better than the profile produced byadministration of a single dose of Solution XIV before each meal.Furthermore, the study shows that administering Solution XIV as a splitdose resulted in lower post-prandial glucose levels than the levelsachieved through administration of a single dose of Solution XIV or asingle dose of injected insulin before each meal. High post-prandialblood glucose levels have been implicated as a risk factor forcardiovascular disease and employing a split dose regimen may serve tominimize this risk.

Whereas particular embodiments of this invention have been describedabove for the purposes of illustration, it will be evident to thoseskilled in the art that numerous variations of the details of thepresent invention may be made without departing from the invention asdefined in the appended claims.

1. A pharmaceutical formulation for absorption through oral mucosaecomprising an effective amount of (a) a pharmaceutical agent in mixedmicellar form, (b) at least one micelle-forming compound selected fromthe group comprising an alkali metal alkyl sulfate and a polyoxyethylenesorbitan monooleate, (c) a block copolymer of polyoxyethylene andpolyoxypropylene, (d) at least one additional micelle-forming compoundchosen from the group comprising trihydroxyoxocholanyl glycine and saltsthereof, glycerin, polyglycerin, lecithin, hyaluronic acid, glycolicacid, lactic acid, chamomile extract, cucumber extract, oleic acid,linoleic acid, linolenic acid, monoolein, monooleates, monolaurates,borage oil, evening primrose oil, menthol, polyglycerin, lysine,polylysine, triolein, polyoxyethylene ethers, polidocanol alkyl ethers,chenodeoxycholate, deoxycholate, alkali metal salicylate,pharmaceutically acceptable edetate, and pharmaceutically acceptablesalts and analogues thereof, and (e) a suitable solvent.
 2. Thepharmaceutical formulation of claim 1 wherein the salt oftrihydroxyoxocholanyl glycine is sodium glycocholate.
 3. Thepharmaceutical formulation of claim 1, wherein the polyoxyethylenesorbitan monooleate is an (x)-sorbitan mono-9-octadecenoatepoly(oxy-1,2-ethanediyl) monooleate.
 4. The pharmaceutical formulationof claim 1, wherein the alkali metal alkyl sulfate is sodium laurylsulfate.
 5. The pharmaceutical formulation of claim 1, wherein the ablock copolymer of polyoxyethylene and polyoxypropylene has thefollowing formula:HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H wherein a=12 and b=20.
 6. Thepharmaceutical formulation of claim 1, wherein the at least oneadditional micelle-forming compound is selected from the groupcomprising sodium glycocholate, glycerin, lecithin, oleic acid,monooleates, polyglycerin, polyoxyethylene ethers, chenodeoxycholate,deoxycholate, lactic acid and pharmaceutically acceptable salts andanalogues thereof.
 7. The pharmaceutical formulation of claim 1, whereinthe at least one additional micelle-forming compound is selected fromthe group comprising sodium glycocholate, glycerin, and polyoxyethyleneethers.
 8. The pharmaceutical formulation of claim 1 comprisingglycerin, sodium glycocholate, sodium lauryl sulfate, and a blockcopolymer of polyoxyethylene and polyoxypropylene having the followingformula:HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H, wherein a=12 and b=20.
 9. Thepharmaceutical formulation of claim 1, wherein the micelle-formingcompounds are each present in a concentration of from about 0.001 to 20wt./wt. %.
 10. The pharmaceutical formulation of claim 9, wherein theblock copolymer of polyoxyethylene and polyoxypropylene is present in aconcentration of from about 0.001 to 3 wt./wt. %.
 11. The pharmaceuticalformulation of claim 9, wherein the micelle-forming compounds are eachpresent in a concentration of from about 0.001 to 1 wt./wt. %.
 12. Thepharmaceutical formulation of claim 1, wherein the micelle size of thepharmaceutical agent is equal to or greater than about 7 microns (μm).13. The pharmaceutical formulation of claim 1, wherein the micelle sizeof the pharmaceutical agent is equal to or less than about 11 microns(μm).
 14. The pharmaceutical formulation of claim 1, wherein thepharmaceutical agent is selected from the group comprising insulin,heparin, low molecular weight heparin (molecular weight less than about5000 daltons), hirulog, hirugen, hirudin, interferons, cytokines, monoand polyclonal antibodies, immunoglobins, chemotherapeutic agents,vaccines, glycoproteins, bacterial toxoids, hormones, calcitonins,glucagon like peptides (GLP-1), large molecular antibiotics (i.e.,greater than about 1000 daltons), protein based thrombolytic compounds,platelet inhibitors, DNA, RNA, gene therapeutics, antisenseoligonucleotides, opioids, narcotics, hypnotics, steroids and painkillers.
 15. The pharmaceutical formulation of claim 14, wherein thepharmaceutical agent is insulin.
 16. The pharmaceutical formulation ofclaim 15, wherein the insulin is present in a concentration of fromabout 0.1 to 12 wt./wt. %.
 17. The pharmaceutical formulation of claim16, wherein the insulin is present in a concentration of from about 0.1to 1 wt./wt. %.
 18. A metered dose non-aerosol dispenser comprising thepharmaceutical formulation of claim
 1. 19. A metered dose aerosoldispenser comprising the pharmaceutical formulation of claim 1 togetherwith a pharmaceutically acceptable propellant.
 20. A method ofadministering a pharmaceutical formulation according to claim 1,comprising spraying the pharmaceutical formulation into an oral cavityof a patient.
 21. The method of claim 20, wherein the pharmaceuticalagent of the pharmaceutical formulation is insulin and from about 35 to104 units of insulin are sprayed before and after each meal.
 22. Themethod of claim 20, further comprising the step of spraying from about14 to about 65 units of insulin into the oral cavity before and after asnack.
 23. The method of claim 20, wherein the pharmaceuticalformulation is sprayed between meals.